WNK1

Chr 12p13.33

WNK lysine deficient protein kinase 1

Aliases:: HSAN2, PPP1R167
MANE:: ENST00000315939.11

OMIM: 605232 ↗NCBI: 65125 ↗Ensembl ↗

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Predicted protein structure

AlphaFold predicted structure

WNK1 · Q9H4A3

v62025-08-01

Predicted Aligned Error matrix for WNK1 — diagonal shows residue index, colour shows pairwise prediction confidence (lower is better) — Predicted Aligned Error

Mean pLDDT

42.7/ 100

Very low

2,382 residues

Confidence breakdown

Very high(≥ 90)11%
Confident(70–90)8%
Low(50–70)2%
Very low(< 50)78%

Open interactive 3D viewer

AlphaFold (Jumper et al., 2021) · CC BY 4.0

Clinical relevance (Genomics England PanelApp)

Diagnostic Grade (Green)

Extreme early-onset hypertension
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Familial dysautonomia
BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy
BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder
BIALLELIC, autosomal or pseudoautosomal
Pain syndromes
BIALLELIC, autosomal or pseudoautosomal
Renal tubulopathies
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Paroxysmal central nervous system disorders
BIALLELIC, autosomal or pseudoautosomal

Disease associations (Open Targets)

hereditary sensory and autonomic neuropathy type 2
0.77
pseudohypoaldosteronism type 2C
0.73
neurodegenerative disease
0.56
hereditary disease
0.53
uterine corpus leiomyoma
0.41
hereditary sensory and autonomic neuropathy
0.38
pseudohypoaldosteronism type 2
0.38
Abnormality of the skeletal system
0.37
urinary tract obstruction
0.31
Sensorineural hearing impairment
0.31

Score is the Open Targets composite evidence score (0-1). Higher = stronger gene-disease association.

Protein function (UniProt)

Serine/threonine-protein kinase WNK1

Serine/threonine-protein kinase component of the WNK1-SPAK/OSR1 kinase cascade, which acts as a key regulator of blood pressure and regulatory volume increase by promoting ion influx (PubMed:15883153, PubMed:17190791, PubMed:31656913, PubMed:34289367, PubMed:36318922). WNK1 mediates regulatory volume increase in response to hyperosmotic stress by acting as a molecular crowding sensor, which senses cell shrinkage and mediates formation of a membraneless compartment by undergoing liquid-liquid phase separation (PubMed:36318922). The membraneless compartment concentrates WNK1 with its substrates, OXSR1/OSR1 and STK39/SPAK, promoting WNK1-dependent phosphorylation and activation of downstream kinases OXSR1/OSR1 and STK39/SPAK (PubMed:15883153, PubMed:16263722, PubMed:17190791, PubMed:19739668, PubMed:21321328, PubMed:22989884, PubMed:25477473, PubMed:34289367, PubMed:36318922). Following activation, OXSR1/OSR1 and STK39/SPAK catalyze phosphorylation of ion cotransporters SLC12A1/NKCC2, SLC12A2/NKCC1, SLC12A5/KCC2 and SLC12A6/KCC3, regulating their activity (PubMed:16263722, PubMed:21321328). Phosphorylation of Na-K-Cl cotransporters SLC12A2/NKCC1 and SLC12A2/NKCC1 promote their activation and ion influx; simultaneously, phosphorylation of K-Cl cotransporters SLC12A5/KCC2 and SLC12A6/KCC3 inhibit their activity, blocking ion efflux (PubMed:19665974, PubMed:21321328). Also acts as a regulator of angiogenesis in endothelial cells via activation of OXSR1/OSR1 and STK39/SPAK: activation of OXSR1/OSR1 regulates chemotaxis and invasion, while STK39/SPAK regulates endothelial cell proliferation (PubMed:25362046). Also acts independently of the WNK1-SPAK/OSR1 kinase cascade by catalyzing phosphorylation of other substrates, such as SYT2, PCF11 and NEDD4L (PubMed:29196535). Mediates phosphorylation of SYT2, regulating SYT2 association with phospholipids and membrane-binding (By similarity). Regulates mRNA export in the nucleus by mediating phosphorylation of PCF11, thereby decreasing the association between PCF11 and POLR2A/RNA polymerase II and promoting mRNA export to the cytoplasm (PubMed:29196535). Acts as a negative regulator of autophagy (PubMed:27911840). Required for the abscission step during mitosis, independently of the WNK1-SPAK/OSR1 kinase cascade (PubMed:21220314). May also play a role in actin cytoskeletal reorganization (PubMed:10660600). Also acts as a scaffold protein independently of its protein kinase activity: negatively regulates cell membrane localization of various transporters and channels, such as SLC4A4, SLC26A6, SLC26A9, TRPV4 and CFTR (By similarity). Involved in the regulation of epithelial Na(+) channel (ENaC) by promoting activation of SGK1 in a kinase-independent manner: probably acts as a scaffold protein that promotes the recruitment of SGK1 to the mTORC2 complex in response to chloride, leading to mTORC2-dependent phosphorylation and activation of SGK1 (PubMed:36373794). Acts as an assembly factor for the ER membrane protein complex independently of its protein kinase activity: associates with EMC2 in the cytoplasm via its amphipathic alpha-helix, and prevents EMC2 ubiquitination and subsequent degradation, thereby promoting EMC2 stabilization (PubMed:33964204)